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Novel mechanistic insights of a small molecule that blocks the ‘funny current’ in the heart: Therapeutic potential

Scientists from the Departments of Physiology, Anatomy & Genetics and Pharmacology at the University of Oxford have discovered that a well-known, generic drug (‘drug X’), the safety of which is well documented, acts as a low-dose, heart rate lowering agent by targeting the if current.

Global killer

Cardiovascular diseases (CVDs) are the principle cause of non-communicable disease related deaths worldwide. In 2008 the World Health Organisation estimated that CVDs led to approximately 17 million deaths worldwide. Whilst mortality rates from CVDs in high-income countries like the United Kingdom continue to fall, it is still the most common cause of death and accounts for more than 900,000 patients per year coupled with approximately one million NHS inpatient bed days. CVDs are also the main cause of death in the EU, killing over two million people annually and costing the economy nearly €192 billion. With ageing populations and unhealthy lifestyles it is projected that the levels of CVD-related morbidity and associated health-economic costs will continue to rise significantly over the next 25 years.

Bradycardic agents

Commonly used treatments for CVDs and related symptoms include β-blockers and calcium-channel blockers but these agents have significant limitations. β-blockers, for example can cause hypotension, cardiac failure, bronchospasm, worsening of asthma symptoms, and rebound flare of angina. It is well established that a high resting heart rate increases the risk of a cardiac event such as arrhythmias and sudden cardiac death. Consequently, agents that induce a reduction in heart rate (bradycardia) without affecting ventricular contractility are of major interest as potential treatments for ischaemic heart disease and heart failure. Ivabradine (Procoralan, Servier Laboratories) is currently the only marketed drug which is a bradycardic agent that selectively and specifically inhibits the cardiac pacemaker If current, which controls the spontaneous diastolic depolarisation in the sinus node and determines heart rate. However, Ivabradine is not without its drawbacks and is known to cause a number of side-effects, most notably a temporary brightness in the field of vision (‘luminous phenomenon’). Furthermore, the clinical utility of Ivabradine is limited in certain patient groups, including children, pregnant women and the visually impaired. Developing new selective heart rate-reducing agents to treat a specific subset of cardiovascular disease patients represents a significant opportunity for further innovation in the field.

Re-purposed drug

Scientists from the Departments of Physiology, Anatomy & Genetics and Pharmacology at the University of Oxford have discovered that a well-known, generic drug (‘drug X’), the safety of which is well documented, acts as a low-dose, heart rate lowering agent by targeting the if current. The initial discovery was made by Dr Rebecca Burton who made a chance observation that drug X induced a reduction in heart rate. Using traditional electrophysiology techniques on isolated sinoatrial node cells the research team of Dr Burton, Professor David Paterson, Professor Derek Terrar, Dr Gil Bubb, Dr Neil Herring and Dr Rebecca Capel have been able to show that drug X acts at very low doses to specifically block the if current, leading to a reduction in heart rate. Further pre-clinical studies funded by an award from the University Challenge Seed Fund which is managed by Isis Innovation using whole atrial preparations and in vivo have confirmed these findings and demonstrated that whilst drug X is a highly effective bradycardic agent it has no apparent effect on blood pressure. These findings suggest that drug X could potentially be of interest in modulation of the If current at appropriate clinical doses for the treatment of a variety of CVDs including systolic heart failure, diastolic heart failure, sinus tachycardia and cardiac syndrome. The well-established safety profile and widespread use of drug X for other indications will greatly facilitate the regulatory route and the scientists are in the process of planning a phase II proof of concept study in patients with mild systolic heart failure as the next step.

Intellectual property

Isis has filed a priority patent application (GB1312386.4 ‘Pharmaceutical Compounds’, 10th July 2013) and the scientific team have compiled a comprehensive pre-clinical data package which will form the basis of translational funding applications and ethical approval for the phase II clinical trial. We would welcome contact from companies who are interested in licensing this technology and developing the next generation of safe, low-dose specific bradycardic agents.